The present invention relates to new multiheterocyclic compounds with a broad spectrum of action having, inter alia, antiosteoporotic, antirestenotic, anticarcinogenic and antiatherosclerotic activity. The present invention moreover relates to the preparation of these compounds and their use for the production of medicaments, and also medicaments comprising them.
WO 97/24119 discloses antiosteoporosis agents which are structurally related to the compounds described here, but do not have a broad spectrum of action of this type.
The compounds on which the present invention is based can be described by the following general formula (I): 
where
R1 and R2
together with the formal double bond bridging them form a phenyl ring or a six-membered aromatic heterocycle having 1 or 2 nitrogen atoms, which is optionally substituted by halogen, nitro, cyano, trifluoromethyl, hydroxyl, (C1-C6)-alkyl, alkoxy, alkoxycarbonyl, amino, carboxyl, phenoxy, aryl, alkylamino, sulfone or sulfonamine, and
R3=
H or (C1-C4)-alkyl, and
A=
O, S, (CH2)n where n=1,2,3 or 4 or Nxe2x80x94R7 where R7=H or (C1-C4)-alkyl, or is absent and
X, Y, Z=
O, S, N, Nxe2x80x94R8 where R8=H, (C1-C6)-alkyl or aryl, or Cxe2x80x94(R9)(R10) where R9, R10=H, (C1-C6)-alkyl or aryl, or Cxe2x80x94(R11) if the X, Y or Z in question is participating in a formal double bond, where R11=H, (C1-C6)-alkyl or aryl, and
D=
O, S, (CH2)n where n=1,2,3 or 4, or Nxe2x80x94R7 where R7=H or (C1-C4)-alkyl, or is absent and
E, G, L=
H, halogen, nitro, cyano, trifluoromethyl, hydroxyl, carboxyl, C1-C6)-alkyl, alkoxy or alkoxycarbonyl, where E, G and L can be identical or different and
R4=
H, (C3-C8)-cycloalkyl, (C1-C6)-alkyl, which is optionally substituted by hydroxyl, (C1-C6)-alkoxy or phenyl, where the latter is optionally in turn substituted on the phenyl ring by halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, trifluoromethoxy or trifluoromethyl, and
R5=
H or (C1-C4)-alkyl and
R6=
H, (C1-C6)-alkyl or benzyl.
Preferred compounds according to the general formula (I) are those where
R1 and R2
together with the formal double bond bridging them form a phenyl ring or a six-membered aromatic heterocycle having 1 or 2 nitrogen atoms, which is optionally substituted by alkoxy or amino, and
R3=
H, and
A=
O, S, (CH2)n where n=1,2,3 or 4 or Nxe2x80x94H, or is absent and
X, Y, Z=
O, S, N, Nxe2x80x94R8 where R8=H, (C1-C6)-alkyl or aryl, or Cxe2x80x94(R9)(R10) where R9, R10=H, (C1-C6)-alkyl or aryl, or Cxe2x80x94(R11) if the X, Y or Z in question is participating in a formal double bond, where R11=H, (C1-C6)-alkyl or aryl, and
D=
O, S, (CH2)n where n=1,2, 3 or 4, or Nxe2x80x94H, or is absent and
E, G, L=
H, and
R4=
H, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, phenylethyl or (C1-C4)-alkyl, which is optionally substituted by hydroxyl or methoxy, and
R5=
H, and
R6=
H or methyl.
Particularly preferred compounds according to the general formula (I) are those where
R1 and R2
together with the formal double bond bridging them form a phenyl ring, and
R3=
H, and
A=
is absent and
Xxe2x95x90O, Yxe2x95x90N and Zxe2x95x90N or Xxe2x95x90N, Yxe2x95x90N and Zxe2x95x90O, S and
D=
is absent and
E, G, L=
H, and
R4=
methyl and
R5=
H, and
R6=
methyl.
The compounds of the general formula (I) according to the invention can be prepared in the following way using process variant (A) or (B):
(A) reaction of a component (a) 
xe2x80x83with a component (b) 
where b is first reacted in the presence of sulfonyl chloride, POCl3 or PCl5 to give the acid chloride and is then reacted with a in the presence of a base in an inert organic solvent, or a coupling of a with b is carried out by means of BOP or carbodiimide reagents, followed by a cyclization reaction which can be effected by means of heat, acids, bases, dehydrating substances and by addition of generally nucleophilic reagents, where, if appropriate, the COOR6 group is finally hydrolyzed and where Q in one of the two components (a) or (b) is oxygen and in the other components corresponds to Z, or
(B) reaction of a component (axe2x80x2) 
xe2x80x83with a component (b) 
where b is first reacted in the presence of sulfonyl chloride, POCl3 or PCl5 to give the acid chloride and then reacted with axe2x80x2 in the presence of a base in an inert organic solvent, or a coupling of axe2x80x2 with b is carried out by means of BOP or carbodiimide reagents, followed by a cyclization reaction which can be effected by means of heat, acids, bases, dehydrating substances and by addition of generally nucleophilic reagents, where, if appropriate, the COOR6 group is finally hydrolyzed and where Q in one of the two components (axe2x80x2) or (b) is oxygen and in the other component corresponds to Z.
Preferably, in process variant (A), for component (a), Xxe2x95x90N, Yxe2x95x90O and Qxe2x95x90NH is employed and for component (b), Qxe2x95x90O is employed and in
process variant (B), for component (axe2x80x2), Xxe2x95x90NH, Yxe2x95x90NH and Qxe2x95x90O is employed and, for component (bxe2x80x2), Qxe2x95x90O is employed.
Particularly preferably, it applies to both process variants that R1 and R2 together with the formal double bond bridging them form a phenyl radical,
R3, R5, E, G, Lxe2x95x90H,
R4, R6=methyl and
A, D=is absent.
The compounds of the formula (I) according to the invention have a surprisingly wide spectrum of pharmacological action.
They can be used as active compounds in medicaments for the reduction of changes to vascular walls and are employed for the treatment of arterial hypertension and atherosclerosis. Moreover, they can be employed for the treatment of coronary heart disorders, cardiac insufficiency, disorders of brain function, ischemic brain disorders, (peripheral) circulation disorders, micro-circulation disorders and thromboses, functional disorders of the kidney and adrenal gland, bronchospastic and vascular system-related disorders of the airways, sodium retention and edemas as well as osteoporosis and carcinoses.
Furthermore, the proliferation and migration of smooth muscle cells plays a decisive part in the occlusion of vessels. The compounds according to the invention are suitable for inhibiting this proliferation and can therefore also be employed for the treatment of restenosis.
The novel active compounds are distinguished pharmacologically by good kinetic parameters. In particular, they have favorable properties with respect to clearance.
The novel active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceutically suitable excipients or solvents. In this case the therapeutically active compound should in each case be present in a concentration of approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, if water is used as a diluent organic solvents can optionally be used as auxiliary solvents.
Administration is carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously.
In the case of parenteral administration, solutions of the active compound using suitable liquid carrier materials can be employed.
In general, it has proven advantageous in the case of intravenous administration to administer amounts from approximately 0.001 to 1 mg/kg, preferably approximately 0.01 to 0.5 mg/kg, of body weight to achieve effective results, and in the case of oral administration the dose is approximately 0.01 to 100 mg/kg, preferably 0.1 to 50 mg/kg, of body weight.
In spite of this, if appropriate, it may be necessary to depart from the amounts mentioned, namely depending on the body weight or the type of application route, on individual behavior toward the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus in some cases it may be adequate to manage with less than the abovementioned minimum amount, while in other cases the upper limits mentioned must be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual doses over the course of the day.
The present invention is illustrated in greater detail below by working examples.
Starting Compound I 
0.877 g of methyl S-7-carboxy-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (Tetrahedron Letters 38, 3131-34, 1997) is stirred under reflux for 1 h with thionyl chloride (40 ml), concentrated and the residue is dissolved in 20 ml of chloroform. The solution obtained is added dropwise to a mixture of 0.53 g of benzimidazole-2-carboxamidoxime (J. Chem. Soc. C, 1967, 28) and chloroform (50 ml), pyridine (0.48 g) and triethylamine (0.30 g). It is stirred at room temperature for 2 h, then concentrated and the residue is taken up in ethyl acetate. After this, washing with water, saturated sodium hydrogencarbonate solution and saturated sodium chloride solution and drying over magnesium sulfate takes place, after concentration an amorphous residue being obtained which is stirred with dichloromethane and filtered off with suction. Recrystallization is carried out from ethanol (0.41 g). The mother liquor is concentrated and chromatographically purified (CH2Cl2; CH2 Cl2/CH3OH=30/1). 0.6 g of the title compound is obtained from the mother liquor.